Project Summary/Abstract Childhood cancers remain a leading cause of death in children between 1 and 14 years of age. Of the childhood cancers, solid tumors are among the least curable. The goal of the proposed Phase I studies will be to develop targeted anti-cancer platinum analogs to treat three childhood tumors: osteosarcoma, rhabdomyosarcoma and neuroblastoma. In the U.S. about 1600 children are diagnosed with these tumors each year with about 400 to 800 dying each year from these diseases. Cisplatin, a first generation platinum analog, together with other drugs are used in the treatment of these solid tumors. However, cisplatin is highly toxic and causes irreversible kidney damage and hearing loss, which is especially devastating in children because it results in lifelong difficulties in communication and learning. Moreover, high doses of cisplatin, which may be curative, cannot be administered, because of the toxicities. The three childhood cancers selected for the proposed studies have high expression levels of the reduced folate carrier, RFC (SLC19A1), likely because of increased requirements for nutrients. Designing therapeutic agents to be transported by RFC confers a promising approach to achieve targeted delivery of anti-cancer agents in tumor cells, which could result in higher activity and reduced toxicity to other tissues. In preliminary studies we designed, synthesized and tested platinum analogs to target RFC. Two lead compounds were identified which exhibited high potencies against osteosarcoma, rhabdomyosarcoma and neuroblastoma cell lines. The overall goal of our studies is to perform pharmacokinetic, toxicity and efficacy studies of these compounds relative to cisplatin in mice. A maximum tolerated dose (MTD), which is the highest dose that does not cause any measurable toxicity in the mice, will be established. The proposed studies will provide high commercialization potential for the lead compounds since both analogs would be poised for critical Investigational New Drug (IND) enabling studies.